Abstract Chronic alcohol consumption is the most common and costly form of substance abuse in the United States and is highly prevalent in persons living with HIV/AIDS (PLWHA). Antiretroviral therapy (ART) has greatly reduced HIV/AIDS mortality, and HIV infection is emerging as a chronic disease with enhanced risk for metabolic comorbidities like insulin resistance and prediabetes. Chronic hazardous alcohol drinking (AUDIT score ?5) is also a risk factor for these comorbidities. Our studies in chronic binge alcohol (CBA) administered simian immunodeficiency virus (SIV)-infected (CBA/SIV) male rhesus macaques (ART-treated and -nave) have shown that dysfunctional skeletal muscle (SKM) is associated with impaired glucose regulation despite normal fasting glycemia. This UH2UH3 application proposes to leverage our ongoing translational study, (P60 AA009803; PI: Molina) Aging in Louisiana: Immunosenescence, hiV, & socioEnvironmental factors (ALIVE) Study in a cohort of in-care adult PLWHA to translate our findings from the macaque model. We propose a combined two phase cross-sectional and prospective study to test the prediction that a higher proportion of PLWHA with AUDIT ?5 with subclinical fasting dysglycemia will present with impaired oral glucose tolerance. We hypothesize that dysfunctional metabolic SKM and loss of mitochondrial homeostatic mechanisms are important mechanisms underlying this metabolic comorbidity. Studies proposed in the UH2 phase aim to validate this ?preintervention? hypothesis. Studies proposed in the UH3 phase will test the hypothesis that SKM metabolic function and mitochondrial homeostasis can be enhanced (or restored) by aerobic exercise, improving glycemic control. The hypotheses to be tested are based on evidence derived from our comprehensive characterization of metabolic dysregulation in CBA/SIV macaques and on preliminary findings obtained from interim analysis of data collected from PLWHA recruited to our ALIVE study. Our bi-directional translational approach ensures relevance of our findings from non-human primates to the human condition. The proposed study will be conducted by an interdisciplinary team of investigators with established expertise on studies of the impact of alcohol on metabolic comorbidities in the SIV/HIV infected host. This project will benefit from the rich scientific environment, and outstanding Experimental and Analytical Resource Cores of the LSUHSC Comprehensive Alcohol Research Center. The expected results should have a profound impact on ameliorating the risk of developing metabolic comorbidities that impose a significant burden on the health care of PLWHA. These study results will serve to inform larger scale interventions promoting a more rigorous approach to identification of at-risk PLWHA that may benefit from preventive measures to increase physical activity and modify behavior leading to improved health, quality of life, and possibly decreased hazardous alcohol drinking.